Protein kinase inhibitors flavopiridol and 7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell chronic lymphocytic leukemia

Compounds that inhibit protein kinases are currently undergoing clinical ev aluation for the treatment of a variety of malignancies, The kinase inhibit ors flavopiridol and 7 hydroxy-staurosporine (UCN-01) were examined for the ir effects on B-cell chronic lymphocytic leukemia (B-CLL) cells in vitro (n = 49), Flavopiridol and UCN-01 induced concentration-dependent apoptosis o f most B-CLL samples tested, with greater than 50% cell killing occurring a t concentrations of less than 1 mu mol/L, and with flavopiridol displaying more potent activity than UCN-01, Flavopiridol (0.1 mu mol/L) and UCN-01 (1 mu mol/L) also induced striking decreases in the levels of the antiapoptos is proteins Mcl-1, X-tinked inhibitor of apoptosis (XIAP), and BAG-1 in nea rly all cases of B-CLL and of Bcl-2 in approximately half of B-CLL specimen s evaluated. In contrast, expression of the pro-apoptotic proteins Bar and Bak was not significantly influenced by these kinase inhibitors. Flavopirid ol-induced decreases in the levels of antiapoptosis proteins Mcl-1 and XIAP preceded apoptosis and were not substantially affected by the addition of caspase inhibitors to cultures. In contrast, UCN-01-stimulated decreases in antiapoptosis proteins were slower, occurred concurrently with apoptosis, and were partially prevented by caspase inhibitors. The findings suggest th at flavopiridol and UCN-01 induce apoptosis of B-CLL cells through differen t mechanisms. The potent apoptotic activities of flavopiridol and UCN-01 ag ainst cultured B-CLL cells suggest that they may be effective as single age nts in the treatment of B-CLL or for sensitizing B-CLL cells to conventiona l cytotoxic drugs. (C) 2000 by The American Society of Hematology.